Penetration of morphine from blood plasma into the central nervous system is regulated by transport barriers which exist at brain capillaries and choroid plexus epithelium. Since brain capillaries are almost totally impermeable to morphine, we have hypothesized that the plasma-choroid plexus-cerebrospinal fluid (CSF) barrier may be the major penetration route for diffusional access of the drug to opiate receptors located at periventricular sites. Evidence to support this hypothesis has been obtained showing that (1) morphine-induced respiratory depression results from penetration of the drug into brain stem by diffusion from CSF; and (2) tolerant rats show a significant decrease in concentration of morphine in both CSF and brain stem to levels which cannot induce respiratory depression in naive animals. Future work is designed to prove that the phenomenon of tolerance to the central respiratory depressant effects of morphine may be mediated by induction of a transport protein in the choroid plexus. Such an event would effectively block penetration of opiates from plasma into CSF during tolerance, and thereby prevent diffusion of effective concentrations of the drug into the microenvironment of respiratory neurons of the brain stem.